July 30, 2008

Chicago -- The first Alzheimer's drug that actually may arrest the progress of the disease showed promising results in early clinical trial research presented Tuesday in Chicago.

The drug, which has been around since the 1930s and is used to treat urinary tract infections and also to make blue ink, allowed people with moderate Alzheimer's disease to remain stable for nearly two years while those who got a placebo continued to decline, according to lead researcher Claude Wischik, a professor of psychiatric gerontology at the University of Aberdeen in Scotland.

The benefit was more than twice that of existing Alzheimer's drugs, said Wischik, who co-founded and holds a financial interest in TauRx Therapeutics, the Singapore company that is funding the research.

Doctors cautioned that the research has not been published in a peer-reviewed journal and is still in a preliminary phase. A larger trial would be required before the drug could be approved in the United States for this use. Wischik said the earliest the drug could be available is 2012, and possibly 2013 if the Food and Drug Administration requires more toxicity testing.

He noted that up to 30% of people taking the drug had diarrhea, and about 25% of people dropped out of the trial because of that side effect.

The mechanism of the drug is based on a controversial theory about what causes Alzheimer's disease, which now affects 5 million Americans, a number expected to spike in the next decade as the baby boom generation moves into old age.

For several years the predominant theory has been that Alzheimer's is caused by the buildup of plaques of beta-amyloid protein between brain cells. But researchers also have known that a different protein, known as tau, can accumulate inside brain cells.

The new clinical trial, which involved 321 people with mild to moderate Alzheimer's in Great Britain and Singapore, tested the drug methylthioninium chloride, or MTC, which helps prevent the buildup of tangles of tau inside brain cells and causes them to burst.

'Phenomenal benefit'

"If this is true, this drug offers benefits that are better than any current therapy," said Mark Sager, a professor of medicine at the University of Wisconsin-Madison and director of the Wisconsin Alzheimer's Institute. "It's a phenomenal benefit."

Sager said the study also raises questions about whether more research effort should be focused on drugs that prevent tau from accumulating in the brain.

"Everybody has banked their money on amyloid," said Sager, who was not a part of the study. "Tau may play a much bigger role in this disease."

Sager and others now suggest that the most effective treatment for Alzheimer's eventually may be a type of drug cocktail, made up of agents targeting tau along with other experimental compounds now in testing, including drugs that prevent beta-amyloid from clumping in the brain.

Existing Alzheimer's drugs only treat symptoms modestly and do not affect the pathology of the disease.

Researchers this week presented several encouraging early clinical trial results at the Alzheimer's Association International Conference on Alzheimer's Disease. That research includes:

- A three-month trial of the drug PBT2, which prevents the accumulation of a toxic form of beta-amyloid by interfering with the protein's ability to interact with copper and zinc. The trial, which was funded by the drug's maker, Prana Biotechnology, involved 78 people and showed improvements on two cognitive tests but not on another test.

- A three-month European trial of a patented "medical food" nutritional drink designed to improve connections, known as synapses, between brain cells. The drug, known as Souvenaid, was tested on 212 people with mild Alzheimer's. It was found to have a significant impact on verbal memory scores, but not other measures.

More results, including several targeting beta-amyloid, also are being presented this week.

"I'm terribly happy there are a lot of approaches being tested," said Marcelle Morrison-Bogorad, director of the neurosciences division of the National Institute of Aging, part of the National Institutes of Health. "I think eventually we are going to have a cocktail of drugs and behavioral things like exercise."

But it is the MTC, which goes under the brand name rember, that has generated much of the excitement at the conference.

The drug is believed to work by dissolving filaments of tau protein inside brain cells.

Using a standard memory and cognitive test, those taking MTC remained nearly stable over a 50-week period, compared with those on a placebo who declined significantly. The benefit amounted to an 81% reduction in cognitive decline in those taking MTC.

One woman in the trial who had stopped using her computer because of her Alzheimer's was able to start using it again, Wischik said.

Wischik said brain imaging studies showed virtually no loss of brain cells in areas typically affected by Alzheimer's, compared with a 7% loss of brain cells in those taking the placebo.

Larger trials needed

However, other researchers not associated with the study cautioned that at least two other phase two clinical trials had shown promise in recent years, but failed to show benefits when larger phase three trials were done.

"It needs to be replicated in larger trials," said Sam Gandy, a professor of neurology and psychiatry at Mount Sinai School of Medicine.

One potential problem with MTC is that desperate families may try to get the drug, which is made in India and is available in the U.S. by prescription and through the Internet, and use it to treat a loved one with Alzheimer's.

Wischik cautioned that the drug has never undergone regulatory scrutiny and it may contain unsafe levels of heavy metals.

"It's an unregulated product of questionable providence," he said.

For the clinical trial, a purified form of the drug was used, he said.

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